The majority of AIDS patients eventually develop AIDS dementia complex, which causes cognitive, motor and behavioral abnormalities. Although AZT can partially reverse the neurological dysfunction, the dose currently used may not be sufficient to suppress the viral replication and prevent the viral re-infection in the CNS. Furthermore, the FDA approved drugs, ddC and ddI, do not penetrate the blood-brain barrier. Therefore, it is critical to develop new and improved anti-HIV agents which penetrate the CNS and suppress viral replication. In this competing continuation application, three priority issues of current AIDS chemotherapy are considered: 1) Brain targeting of ddC, dI and newly discovered anti-HIV agents in our laboratories- In order to target the brain, several enzyme systems, which include xanthine oxidase, adenosine deaminase, and P450 reductase system, will be exploited to biotransform the proposed prodrugs in vivo. Positive preliminary results have already been obtained in vivo (mice) with several key compounds during the current funding period and further in-depth pharmacokinetic studies, including in rhesus monkeys, are proposed in this application; 2) Targeting of the lymphatic system- Although the clinical course of HIV infection is characterized as latent for a prolonged period after primary infection, HIV replication continues at high levels in the lymphatic system. Therefore, it is critical to develop anti-HIV agents that preferentially penetrate the lymphoid organs. A recent report suggests some types of phospholipid conjugates of nucleoside preferentially penetrate the lymphoid organs. Therefore, synthesis of several anti-HIV nucleoside conjugates of phospholipid is proposed and their pharmacokinetic properties will be characterized. A preliminary pharmacokinetic study with AZT in the lymphatic system of mice has recently been completed to assess the currently available drug regimen, which will be compared with the synthesized prodrugs in vivo; 3) To study drug resistance- Drug resistance is one of the key issues in AIDS chemotherapy today. Therefore, it is critical to understand the molecular mechanism and to study methods that can delay or prevent the development of drug resistance. As a continuation of our efforts to develop anti-HIV agents that are not cross resistant with the existing regimens, newly discovered anti-HIV nucleosides in our laboratories will be studied for resistant characteristics to the current anti-HIV agents, as well as developing resistant viruses to the newly discovered anti-HIV nucleosides. The overall goal of this application is to discover new anti-HIV prodrugs with improved pharmacological and virological profiles for clinical use.